The identification of complex small molecules, which bind to receptors, proteins and enzymes, has been expedited through the use of combinatorial methods and the development of high throughput screening. The identified biological targets serve as powerful tools for pharmacological studies and are essential for drug development. The long term objectives of this proposed research are: to make creative contributions to the catalytic asymmetric synthesis of multicomponent coupling reactions namely the Ugi four component coupling reaction, to elucidate the general mechanism of the reaction, to develop a complex small molecule library incorporating appending processes, differentiating processes and folding processes so that from one reaction process, many different skeletal structures can be realized, and to determine the interaction that the range of compounds have on receptors, proteins and enzymes. Through the use of chiral Lewis acids, stereo-diversity will be incorporated into a tricyclic-lactam intermediate whereby building block diversity, through appending processes, will decorate this core structure. A metathesis reaction will reveal a folding process producing compounds with varying skeletal arrays. These complex small molecules will be utilized in a chemical genetics approach to perturb biological function through cytoblot assays and decipher disease pathways by utilizing the technique of high throughput screening. Both phenotypic screens and protein-binding assays will be performed to generate direct leads for drug development and cancer treatment.